Pulmonary hypertension treatment

ABSTRACT

Disclosed herein is a therapeutically active agent usable in the treatment of pulmonary arterial hypertension (PAH), for use in the treatment of pulmonary arterial hypertension, as well as methods of treating PAH, said treatment and methods comprising administering such an active agent and effecting pulmonary artery denervation in the subject. In some aspects, a sub-therapeutically effective amount of the active agent is administered. In some aspects, the method is devoid of administering such an active agent for at least one month subsequent to the denervation. Further disclosed is a method of treating PAH comprising determining a responsiveness of the subject to at least one therapeutically active agent usable in treating PAH; and effecting pulmonary artery denervation in a subject responsive to the active agent(s).

RELATED APPLICATIONS

This application claims the benefit of priority under 35 USC § 119(e) ofU.S. Provisional Patent Application Ser. No. 62/473,532 filed 20 Mar.2017, Provisional Patent Application No. 62/473,545 filed 20 Mar. 2017and Provisional Patent Application No. 62/473,512 filed 20 Mar. 2017,the contents of which are incorporated herein by reference in theirentirety.

This application is related to a PCT Application entitled “PULMONARYHYPERTENSION TREATMENT METHOD AND/OR SYSTEM” of the same applicant,filed on the same filing date as this application.

This application is also related to PCT Application No.PCT/IL2018/050316 of the same applicant, filed on the same filing dateas this application.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to therapy,and more particularly, but not exclusively, to a treatment of pulmonaryarterial hypertension.

Pulmonary arterial hypertension (PAH) generally involves the narrowingof blood vessels connected to and within the lungs, which may result infibrosis of the blood vessels over time. As with other forms ofpulmonary hypertension, the increased workload of the heart causeshypertrophy of the right ventricle, and ultimately right heart failure.

The following forms of PAH have been internationally recognized:idiopathic PAH; heritable PAH (associated with a BMPR2 mutation, with anALK1 or endoglin mutation, or with an unknown cause); drug-induced andtoxin-induced PAH; PAH associated with connective tissue disease, HIVinfection, portal hypertension, congenital heart diseases,schistosomiasis or chronic hemolytic anemia; persistent pulmonaryhypertension of the newborn; and pulmonary veno-occlusive disease (POVD)and/or pulmonary capillary hemangiomatosis (PCH) [Simonneau et al., J AmColl Cardiol 2009, 54:S43-S54].

Current therapies in pulmonary arterial hypertension (PAH) target threeseparate signaling pathways: the prostaglandin pathway, endothelinpathway, and nitric oxide/guanylate cyclase pathway [Sitbon & Gaine, EurRespir Rev 2016, 25:408-417; Galie et al., Eur Heart J 2016, 37:67-119].

Prostacyclin (prostaglandin I₂) is a potent vasodilator which inducesrelaxation of vascular smooth muscle, as well as being a potentinhibitor of platelet aggregation. Dysregulation of the prostacyclinmetabolic pathway has been reported in patients with PAH.

Prostanoids (synthetic prostacyclin analogues) used in treatment of PAHinclude epoprostenol (synthetic prostacyclin) for intravenousadministration; iloprost, for administration by inhalation orintravenous administration; beraprost, for oral administration; andtreprostinil, for administration by inhalation, or oral, subcutaneous orintravenous administration.

Selexipag is an additional orally available drug for use in treatingPAH. Selexipag and its active metabolite are selective prostacyclinreceptor (IP) agonists. Although the mode of action of selexipag issimilar to those of prostanoids, selexipag is chemically distinct fromprostanoids and characterized by different pharmacology.

The endothelin (ET) system has an important role in the pathogenesis ofPAH. Activation of the endothelin system has been reported in bothplasma and lung tissue of PAH patients. Endothelin receptor antagonistsused in treatment of PAH (especially mild to moderate PAH) includebosentan, ambrisentan, and macitentan. Ambrisentan is a selectiveinhibitor of type A endothelin receptor (ET_(A)), and bosentan andmacitentan inhibit both type A (ET_(A)) and type B (ET_(B)) endothelinreceptor.

Nitric oxide (NO) promotes vasodilation by activating soluble guanylatecyclase (sGC), an enzyme which synthesizes cyclic GMP (cGMP), a mediatorof vasodilation.

Phosphodiesterase type-5 (PDE-5) inhibitors inhibit the breakdown ofcyclic GMP (by PDE-5), thereby augmenting signaling downstream of nitricoxide, resulting in pulmonary vasodilation and anti-proliferation. PDE-5inhibitors used for treatment of PAH include sildenafil, tadalafil andvardenafil.

Riociguat is a soluble guanylate-cyclase stimulator (sGCS), whichincreases sGC activity, thereby promoting vasodilation and inhibitingsmooth muscle proliferation, leukocyte recruitment, plateletaggregation, and vascular remodeling. Riociguat is used to treat PAH andchronic thromboembolic pulmonary hypertension.

Sitbon & Gaine [Eur Respir Rev 2016, 25:408-417] and the 2015 EuropeanSociety of Cardiology (ESC)/European Respiratory Society (ERS)Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension[Galie et al., Eur Heart J 2016, 37:67-119] describe various combinationtherapies which target two or three of the abovementioned pathways, andwhich are recommended therein for treating PAH.

Chen et al. [J Am Coll Cardiol 2013, 62:1092-1100] report the use ofpulmonary artery denervation using an ablation catheter to treatidiopathic PAH in human subjects. All subjects had received a diureticand beraprost, with either sildenafil, bosentan or digoxin, and wereidentified as not responding optimally to therapy prior to denervation.

International Patent Application Publication WO 2016/084081 describesdevices and methods for treating pulmonary hypertension, using acatheter device introduced to the pulmonary artery lumen to selectivelymodify nerve activity by emitting ultrasound energy.

Additional background art includes Galie & Manes [J Am Coll Cardiol2013, 62:1101-1102], and U.S. Patent Application Publication No.2013/0204068.

SUMMARY OF THE INVENTION

According to an aspect of some embodiments of the invention, there isprovided a therapeutically active agent usable in the treatment ofpulmonary arterial hypertension, for use in the treatment of pulmonaryarterial hypertension in a subject in need thereof, wherein thetreatment comprises administering the active agent to the subject andeffecting pulmonary artery denervation in the subject.

According to an aspect of some embodiments of the invention, there isprovided a method of treating pulmonary arterial hypertension in asubject in need thereof, the method comprising:

a) determining a responsiveness of the subject to at least onetherapeutically active agent usable in treating pulmonary arterialhypertension; and

b) effecting pulmonary artery denervation in a subject responsive to theat least one therapeutically active agent,

thereby treating the pulmonary arterial hypertension.

According to an aspect of some embodiments of the invention, there isprovided a method of treating pulmonary arterial hypertension in asubject in need thereof, the method comprising:

a) effecting pulmonary artery denervation in the subject; and

b) administering to the subject at least one therapeutically activeagent usable in treating pulmonary arterial hypertension,

wherein the administering is at a sub-therapeutically effective amount,

thereby treating the pulmonary arterial hypertension.

According to an aspect of some embodiments of the invention, there isprovided a method of treating pulmonary arterial hypertension in asubject in need thereof, the method comprising effecting pulmonaryartery denervation in the subject,

the method being devoid of administering to the subject atherapeutically active agent usable in the treatment of pulmonaryarterial hypertension for a time period of at least one month subsequentto the denervation,

thereby treating the pulmonary arterial hypertension.

According to some of any of the embodiments of the invention, the atleast one therapeutically active agent is selected from the groupconsisting of an anticoagulant, a prostacyclin receptor agonist, anendothelin inhibitor, and a guanylate cyclase activity enhancer.

According to some of any of the embodiments of the invention, thetherapeutically active agent comprises a prostacyclin receptor agonist.

According to some of any of the embodiments of the invention relating toa therapeutically active agent which comprises prostacyclin receptoragonist, the at least one therapeutically active agent further comprisesan endothelin inhibitor.

According to some of any of the embodiments of the invention relating toa therapeutically active agent which prostacyclin receptor agonist, theat least one therapeutically active agent further comprises a guanylatecyclase activity enhancer.

According to some of any of the embodiments of the invention relating toa treatment involving a prostacyclin receptor agonist, the treatmentfurther comprises administering an endothelin inhibitor.

According to some of any of the embodiments of the invention relating toa treatment involving a prostacyclin receptor agonist, the treatmentfurther comprises administering a guanylate cyclase activity enhancer.

According to some of any of the embodiments of the invention, thetherapeutically active agent comprises an endothelin inhibitor.

According to some of any of the embodiments of the invention relating toa therapeutically active agent which comprises an endothelin inhibitor,the at least one therapeutically active agent further comprises aguanylate cyclase activity enhancer.

According to some of any of the embodiments of the invention relating toa treatment involving an endothelin inhibitor, the treatment furthercomprises administering a prostacyclin receptor agonist.

According to some of any of the embodiments of the invention relating toa treatment involving an endothelin inhibitor, the treatment furthercomprises administering a guanylate cyclase activity enhancer.

According to some of any of the embodiments of the invention, thetherapeutically active agent comprises a guanylate cyclase activityenhancer.

According to some of any of the embodiments of the invention relating toa therapeutically active agent which comprises a guanylate cyclaseactivity enhancer, the at least one therapeutically active agent furthercomprises a prostacyclin receptor agonist.

According to some of any of the embodiments of the invention relating toa treatment involving a guanylate cyclase activity enhancer, thetreatment further comprises administering a prostacyclin receptoragonist.

According to some of any of the embodiments of the invention relating toa treatment involving a guanylate cyclase activity enhancer, thetreatment further comprises administering an endothelin inhibitor.

According to some of any of the embodiments of the invention, thetherapeutically active agent comprises an anticoagulant.

According to some of any of the embodiments of the invention relating toa therapeutically active agent which comprises an anticoagulant, the atleast one therapeutically active agent further comprises at least onetherapeutically active agent selected from the group consisting of aprostacyclin receptor agonist, an endothelin inhibitor, and a guanylatecyclase activity enhancer.

According to some of any of the embodiments of the invention relating toa treatment involving an anticoagulant, the treatment further comprisesadministering at least one therapeutically active agent selected fromthe group consisting of a prostacyclin receptor agonist, an endothelininhibitor, and a guanylate cyclase activity enhancer.

According to some of any of the embodiments of the invention, theanticoagulant is selected from the group consisting of warfarin,acenocoumarol, dicoumarol, ethylbiscoumacetate, phenprocoumon,tecarfarin, anisindione, fluindione, phenindione, atromentin, a heparin,fondaparinux, idraparinux, idrabiotaparinux, apixaban, betrixaban,darexaban, edoxaban, eribaxaban, letaxaban, otamixaban, rivaroxaban,hirudin, lepirudin, bivalirudin, desirudin, argatroban, inogatran,dabigatran, melagatran, ximelagatran, antithrombin, batroxobin,hementin, and vitamin E.

According to some of any of the embodiments of the invention, theprostacyclin receptor agonist is selected from the group consisting ofprostacyclin (epoprostenol), iloprost, beraprost, treprostinil andselexipag.

According to some of any of the embodiments of the invention, theendothelin inhibitor comprises a selective ET_(A) receptor antagonist,optionally ambrisentan.

According to some of any of the embodiments of the invention, theendothelin inhibitor comprises a dual ET_(A)/ET_(B) receptor antagonist,optionally bosentan and/or macitentan.

According to some of any of the embodiments of the invention, theguanylate cyclase activity enhancer is selected from the groupconsisting of sildenafil, tadalafil, vardenafil and riociguat.

According to some of any of the embodiments of the invention relating toa treatment, the treatment comprises administering the active agentprior to and/or subsequent to the denervation.

According to some of any of the embodiments of the invention, theadministering is of a therapeutically effective amount of thetherapeutically active agent.

According to some of any of the embodiments of the invention relating toa treatment, the treatment comprises administering a sub-therapeuticallyeffective amount of the therapeutically active agent subsequent to thedenervation.

According to some of any of the embodiments of the invention relating toa treatment, the treatment comprises administering the active agentprior to the denervation, the treatment being devoid of administeringthe active agent for a time period of at least one month subsequent tothe denervation.

According to some of any of the embodiments of the invention, the methodor treatment described herein is devoid of administering to the subjectthe therapeutically active agent usable in the treatment of pulmonaryarterial hypertension for a time period of at least one year subsequentto the denervation.

According to some of any of the embodiments of the invention relating toa sub-therapeutically effective amount, administering thesub-therapeutically effective amount comprises administering,subsequently to the denervation, a dosage of at least onetherapeutically active agent which is lower than a dosage of the agentadministered to the subject prior to the denervation.

According to some of any of the embodiments of the invention relating toa sub-therapeutically effective amount, administering thesub-therapeutically effective amount comprises administering,subsequently to the denervation, fewer therapeutically active agentsthan are administered to the subject prior to the denervation, whereinat least two therapeutically active agent usable in treating pulmonaryarterial hypertension are administered to the subject prior to thedenervation.

According to some of any of the embodiments of the invention, effectingthe pulmonary artery denervation comprises thermally damaging nervetissue associated with a main pulmonary artery.

According to some of any of the embodiments of the invention, thermallydamaging nerve tissue comprises selectively damaging nerves that are notcoated by myelin, by emitting energy at a frequency, intensity andduration sufficient to damage only nerves that are not coated by myelin,by producing a predetermined temperature profile in the treated tissue,the temperature profile ranging between 47-57° C.

According to some of any of the embodiments of the invention, thermallydamaging nerve tissue is effected by cryotherapy and/or by emittingenergy from at least one energy-emitting device introduced into thebody.

According to some of any of the embodiments of the invention, the energyis selected from the group consisting of ultrasound energy and monopolaror bipolar radiofrequency energy.

According to some of any of the embodiments of the invention, the energycomprises unfocused ultrasound energy.

According to some of any of the embodiments of the invention, effectingthe pulmonary artery denervation comprises introducing a catheter devicecomprising the at least one energy-emitting device into a main pulmonaryartery lumen.

According to some of any of the embodiments of the invention, theenergy-emitting device is a transceiver, and effecting the pulmonaryartery denervation further comprises:

receiving, using the at least one energy-emitting transceiver, echosignals reflected from non-targeted tissue following emission of energyby the at least one transceiver;

analyzing the received echo signals to identify at least one of a typeand location of the non-targeted tissue relative to the at least onetransceiver; and

emitting energy from the at least one transceiver in accordance with theanalyzing, to modify nerve activity without substantially damaging theidentified non-targeted tissue.

According to some of any of the embodiments of the invention, effectingthe pulmonary artery denervation further comprises:

positioning the at least one energy-emitting device within the leftpulmonary artery, right pulmonary artery and/or pulmonary artery trunkat a location which is in between the first bifurcation of the leftpulmonary artery and the first bifurcation of the right pulmonaryartery,

wherein thermally damaging nerve tissue comprises emitting energy havingparameters selected to damage nerves only within a distance window ofbetween 0.2 mm and 10 mm from the intimal aspect of the pulmonary arterywall when the at least one device is positioned at the aforementionedlocation.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention. In this regard, thedescription taken with the drawings makes apparent to those skilled inthe art how embodiments of the invention may be practiced.

In the drawings:

FIG. 1 is a table showing a protocol of a study for determining aneffect of denervation in combination with drug therapy, according tosome embodiments of the invention.

FIG. 2 is a flow chart for a protocol of a study for determining aneffect of denervation in combination with drug therapy, according tosome embodiments of the invention.

FIG. 3 is a table showing a protocol of a study for determining aneffect of denervation in combination with drug therapy, according tosome embodiments of the invention.

FIG. 4 is a flow chart for a protocol of a study for determining aneffect of denervation in combination with drug therapy, according tosome embodiments of the invention.

FIGS. 5A-5D present column charts showing changes in mean pulmonaryarterial pressure (mPAP) (FIG. 5A), cardiac index (FIG. 5B), pulmonaryvascular resistance (PVR) (FIG. 5C), and right arterial pressure (RAP)(FIG. 5D), 4 months after denervation treatment according to someembodiments of the invention, in comparison with baseline levels.

FIG. 6 is a column chart showing changes in 6-minute walking distance(6MWD) 4 months after denervation treatment according to someembodiments of the invention, in comparison with baseline levels.

FIG. 7 is a column chart showing changes in activity, as determined bythe number of steps detected by actigraphy, 4 months after denervationtreatment according to some embodiments of the invention, in comparisonwith baseline levels.

FIG. 8 is a column chart showing changes in quality of life, asdetermined by an emPHasis-10 questionnaire score 4 months afterdenervation treatment according to some embodiments of the invention, incomparison with baseline levels (lower score is associated with higherquality of life).

FIG. 9 is a column chart showing changes in pulmonary vascularresistance (PVR) in comparison with baseline levels 4 months afterdenervation treatment, in a group of patients receiving ananti-coagulation medication and in a group of patients that did notreceive the anti-coagulation medication, according to some embodimentsof the invention.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to therapy,and more particularly, but not exclusively, to a treatment of pulmonaryarterial hypertension.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details set forth in the following description orexemplified by the Examples. The invention is capable of otherembodiments or of being practiced or carried out in various ways.

While investigating the effects of pulmonary artery denervation onpulmonary arterial hypertension, the present inventors have uncovereddrug treatments which are particularly effective in combination withdenervation.

The present inventors have further uncovered novel regimens forproviding improved treatment of pulmonary arterial hypertension and/orfor identifying subject populations with enhanced responsiveness todenervation.

While reducing the present invention to practice, the inventors haveshown that denervation is effective in providing a considerableadditional therapeutic effect in treating pulmonary arterialhypertension in subjects already undergoing drug therapy.

Without being bound by any particular theory, it is believed that drugtreatment are particularly useful at targeting small distal pulmonaryartery vessels, whereas denervation procedures are particularly usefulat improving proximal pulmonary artery compliance, such that the drugadministration and denervation procedures complement one another. It isfurther believed that the drug treatment influences vasodilation andremodeling processes, and the denervation reduces right ventricularafterload.

The inventors have further shown that subjects being treated (forpulmonary arterial hypertension) with anticoagulants are particularlyresponsive to denervation.

According to an aspect of some embodiments of the invention, there isprovided a therapeutically active agent usable in the treatment ofpulmonary arterial hypertension (PAH) (e.g., an agent according to anyof the respective embodiments described herein), for use in thetreatment of PAH in a subject in need thereof, wherein the treatmentcomprises administering the active agent to the subject and effectingpulmonary artery denervation (e.g., according to any of the respectiveembodiments described herein) in the subject.

According to an aspect of some embodiments of the invention, there isprovided a use of a therapeutically active agent usable in the treatmentof pulmonary arterial hypertension (PAH) (e.g., an agent according toany of the respective embodiments described herein) in the manufactureof a medicament for use in the treatment of PAH in a subject in needthereof, wherein the treatment comprises administering the active agentto the subject and effecting pulmonary artery denervation (e.g.,according to any of the respective embodiments described herein) in thesubject.

According to an aspect of some embodiments of the invention, there isprovided a method of treating pulmonary arterial hypertension (PAH) in asubject in need thereof. The method comprises: a) effecting pulmonaryartery denervation in the subject (e.g., according to any of therespective embodiments described herein); and b) administering to thesubject at least one therapeutically active agent usable in thetreatment of PAH (e.g., according to any of the respective embodimentsdescribed herein).

According to an aspect of some embodiments of the invention, there isprovided a use of a device configured for effecting pulmonary arterydenervation (e.g., according to any of the respective embodimentsdescribed herein) in the treatment of pulmonary arterial hypertension(PAH) in a subject in need thereof, wherein the treatment comprisesadministering at least one therapeutically active agent usable in thetreatment of PAH (e.g., according to any of the respective embodimentsdescribed herein) and effecting pulmonary artery denervation in thesubject.

Therapeutically Active Agent(s):

Examples of therapeutically active agents usable in the treatment of PAH(according to any one of the embodiments described herein) include,without limitation, anticoagulants, prostacyclin receptor agonists,endothelin inhibitors, and guanylate cyclase activity enhancers (asthese terms are defined herein).

In some embodiments of any of the respective embodiments describedherein, the therapeutically active agent comprises an anticoagulant. Insome embodiments, denervation (e.g., according to any of the respectiveembodiments described herein) acts in synergy with an anticoagulant intreating pulmonary arterial hypertension.

In some embodiments of any of the respective embodiments describedherein, the only therapeutically active agent utilized (according to anyone of the embodiments described herein) is an anticoagulant.

In some embodiments of any of the respective embodiments describedherein, an anticoagulant is utilized (according to any one of theembodiments described herein) in combination with an active agent otherthan an anticoagulant, for example, a prostacyclin receptor agonist, anendothelin inhibitor and/or a guanylate cyclase activity enhancer (e.g.,according to any of the respective embodiments described herein).

Anticoagulants include, without limitation, vitamin K antagonists (e.g.,coumarin derivatives and/or 1,3-inandione derivatives), heparin(optionally low molecular weight heparin) and derived substances, directXa inhibitors, direct thrombin inhibitors, antithrombin, batroxobin,hementin and vitamin E. In some embodiments of any of the embodimentsdescribed herein relating to an anticoagulant, the anticoagulant is avitamin K antagonist, heparin or derived substance, direct Xa inhibitor,and/or direct thrombin inhibitor.

Examples of vitamin K antagonists include, without limitation,4-hydroxycoumarin derivatives such as warfarin, acenocoumarol,dicoumarol, ethylbiscoumacetate, phenprocoumon and tecarfarin;1,3-inandione derivatives such as anisindione, fluindione andphenindione; and atromentin. Warfarin, acenocoumarol and phenprocoumonare examples of relatively common vitamin K antagonists. Warfarin is anexemplary vitamin K antagonist.

Examples of heparins and derived substances include, for example, lowmolecular weight heparins such as bemiparin, nadroparin, reviparin,enoxaparin, parnaparin, certoparin, dalteparin and tinzeparin; andoligosaccharides such as fondaparinux, idraparinux and idrabiotaparinux.Enoxaparin and fondaparinux are exemplary anticoagulants which are a lowmolecular weight heparin or heparin-derived substance.

Examples of direct Xa inhibitors (which act directly on Factor X)include, without limitation, rivaroxaban, apixaban, betrixaban,darexaban, edoxaban, eribaxaban, letaxaban, and otamixaban. Rivaroxaban,apixaban, edoxaban and betrixaban are examples of relatively commondirect Xa inhibitors. Rivaroxaban, apixaban and edoxaban are exemplarydirect Xa inhibitors.

Examples of direct thrombin inhibitors (which directly inhibit thrombin)include, without limitation, bivalent direct thrombin inhibitors such ashirudin, bivalirudin, lepirudin and desirudin; and univalent directthrombin inhibitors such as argatroban, inogatran, melagatran anddabigatran. Bivalirudin, lepirudin, desirudin, argatroban, anddabigatran are examples of relatively common direct thrombin inhibitors.Dabigatran is an exemplary direct thrombin inhibitor.

In some embodiments of any of the respective embodiments describedherein, the anticoagulant is orally administrable. Examples of orallyadministrable anticoagulants include, without limitation, rivaroxaban,apixaban, edoxaban, betrixaban, dabigatran, and vitamin K antagonistswhich are 4-hydroxycoumarin or 1,3-inandione derivatives (according toany of the respective embodiments described herein).

In some embodiments of any of the respective embodiments describedherein, the anticoagulant is intravenously and/or subcutaneouslyadministrable, for example, administrable by IV (intravenous) pumpand/or subcutaneous (SC) pump. Examples of intravenously and/orsubcutaneously administrable prostacyclin receptor agonists include,without limitation, hirudin, bivalirudin, lepirudin, desirudin,batroxobin, and heparin and derived substances, according to any of therespective embodiments described herein.

In some embodiments of any of the respective embodiments describedherein, a dosage of anticoagulant is sufficient to maintain an ACT(activated clotting time) higher than 270 seconds, for example, before,during and/or after a denervation treatment. In some embodiments, theACT is higher than 275 seconds or higher than 280 seconds or anyintermediate, smaller or larger value, for example, before, duringand/or after a denervation treatment.

In some embodiments of any of the respective embodiments describedherein, the therapeutically active agent comprises a prostacyclinreceptor agonist. In some embodiments, denervation (e.g., according toany of the respective embodiments described herein) acts in synergy witha prostacyclin receptor agonist in treating pulmonary arterialhypertension.

In some embodiments of any of the respective embodiments describedherein, the only therapeutically active agent utilized (according to anyone of the embodiments described herein) is a prostacyclin receptoragonist.

In some embodiments of any of the respective embodiments describedherein, a prostacyclin receptor agonist is utilized (according to anyone of the embodiments described herein) in combination with an activeagent other than a prostacyclin receptor agonist, for example, ananticoagulant, an endothelin inhibitor and/or a guanylate cyclaseactivity enhancer (e.g., according to any of the respective embodimentsdescribed herein).

Prostacyclin receptor agonists include prostacyclin (includingepoprostenol) and prostacyclin analogues (also referred to as“prostanoids”), as well as agonists which are structurally unrelated toprostacyclin.

Examples of prostanoids include, without limitation, prostacyclin,AFP-07(5Z-[(3aR,4R,5R,6aS)-3,3-difluorohexahydro-5-hydroxy-4-[(1E,3S,4S)-3-hydroxy-4-methyl-1-nonen-6-ynyl]-2H-cyclopenta[b]furan-2-ylidene]-pentanoicacid), alprostadil, beraprost, carbacyclin, cicaprost, iloprost,isocarbacyclin, taprostene, and treprostinil. Prostacyclin, iloprost,beraprost and treprostinil are examples of relatively commonprostanoids.

Selexipag, ralinepag, ACT-333679 (a metabolite of selexipag), BMY-45778([3-(4,5-diphenyl[2,4′-bioxazol]-5′-yl)phenoxy] acetic acid) and TRA-418({4-[2-(1,1-diphenylethylsulfanyl)-ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxy}-aceticacid) are non-limiting examples of a prostacyclin receptor agonist whichis not a prostanoid. Selexipag is an example of a relatively commonprostacyclin receptor agonist.

In some embodiments of any of the respective embodiments describedherein, the prostacyclin receptor agonist is orally administrable.Examples of orally administrable prostacyclin receptor agonists include,without limitation, beraprost, treprostinil and selexipag.

In some embodiments of any of the respective embodiments describedherein, the prostacyclin receptor agonist is administrable byinhalation. Examples of prostacyclin receptor agonists administrable byinhalation include, without limitation, treprostinil and iloprost.

In some embodiments of any of the respective embodiments describedherein, the prostacyclin receptor agonist is intravenouslyadministrable, for example, administrable by IV (intravenous) pump.Examples of intravenously administrable prostacyclin receptor agonistsinclude, without limitation, prostacyclin, treprostinil, and iloprost.

In some embodiments of any of the respective embodiments describedherein, the prostacyclin receptor agonist is subcutaneouslyadministrable, for example, administrable by subcutaneous (SC) pump.Treprostinil is a non-limiting example of a subcutaneously administrableprostacyclin receptor agonist.

In some embodiments of any of the respective embodiments describedherein, the therapeutically active agent comprises an endothelininhibitor. In some embodiments, denervation (e.g., according to any ofthe respective embodiments described herein) acts in synergy with anendothelin inhibitor in treating pulmonary arterial hypertension.

In some embodiments of any of the respective embodiments describedherein, the only therapeutically active agent utilized (according to anyone of the embodiments described herein) is an endothelin inhibitor.

In some embodiments of any of the respective embodiments describedherein, an endothelin inhibitor is utilized (according to any one of theembodiments described herein) in combination with an active agent otherthan an endothelin inhibitor, for example, an anticoagulant, aprostacyclin receptor agonist and/or a guanylate cyclase activityenhancer (e.g., according to any of the respective embodiments describedherein).

Herein, the term “endothelin inhibitor” refers to an agent whichinhibits a biological activity of an endothelin (e.g., endothelin-1,endothelin-2 and/or endothelin-3); for example, by interacting with anendothelin receptor (e.g., endothelin receptor antagonists) and/or byinteracting with endothelin (e.g., by binding to endothelin) and/or byinhibiting endothelin secretion, as well as prodrugs of agents whichexhibit such interactions.

In some embodiments of any of the respective embodiments describedherein, the endothelin inhibitor is an endothelin receptor antagonist;optionally an antagonist of endothelin receptor type A (ET_(A)),endothelin receptor type B (ET_(B)) or both ET_(A) and ET_(B) (dualantagonists).

Examples of ET_(A) receptor antagonists (e.g., selective antagonists)include, without limitation, ambrisentan, atrasentan, BQ-123,sitaxentan, and zibotentan. Ambrisentan is an example of an ET_(A)antagonist particularly suitable for treating PAH, according to someembodiments.

Examples of dual antagonists of ET_(A)/ET_(B) receptor include, withoutlimitation, bosentan, macitentan and tezosentan. Bosentan and macitentanare examples of dual antagonists particularly suitable for treating PAH,according to some embodiments.

In some embodiments of any of the respective embodiments describedherein, the therapeutically active agent comprises a guanylate cyclaseactivity enhancer. In some embodiments, denervation (e.g., according toany of the respective embodiments described herein) acts in synergy witha guanylate cyclase activity enhancer in treating pulmonary arterialhypertension.

In some embodiments of any of the respective embodiments describedherein, the only therapeutically active agent utilized (according to anyone of the embodiments described herein) is a guanylate cyclase activityenhancer.

In some embodiments of any of the respective embodiments describedherein, a guanylate cyclase activity enhancer is utilized (according toany one of the embodiments described herein) in combination with anactive agent other than a guanylate cyclase activity enhancer, forexample, an anticoagulant, a prostacyclin receptor agonist and/or anendothelin inhibitor (e.g., according to any of the respectiveembodiments described herein).

Herein, the term “guanylate cyclase activity enhancer” refers to anagent which enhances a biological activity of guanylate cyclase; forexample, by increasing a concentration of cyclic GMP (a compound formedby guanylate cyclase) by interacting with guanylate cyclase so as toincrease cyclic GMP production (e.g., guanylate cyclase activatorsand/or stimulators) and/or by inhibiting breakdown of cyclic GMP (e.g.,phosphodiesterase inhibitors), as well as prodrugs of agents whichexhibit such interactions.

In some embodiments of any of the respective embodiments describedherein, the guanylate cyclase activity enhancer is an inhibitor ofphosphodiesterase 5 (a cyclic GMP-specific phosphodiesterase).

Examples of phosphodiesterase 5 (PDE5) inhibitors include, withoutlimitation, avanafil, benzamidenafil, dasantafil, lodenafil,mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, and zaprinast.Sildenafil, tadalafil and vardenafil are examples of PDE5 inhibitorsparticularly suitable for treating PAH, according to some embodiments.

In some embodiments of any of the respective embodiments describedherein, the guanylate cyclase activity enhancer is an activator and/orstimulator of guanylate cyclase.

Examples of guanylate cyclase activators and/or stimulators include,without limitation, riociguat and cinaciguat. Riociguat is an example ofa guanylate cyclase activity stimulator particularly suitable fortreating PAH, according to some embodiments.

Regimen and/or Patient Population:

In some embodiments of any of the embodiments described herein relatingto a treatment and/or method, the treatment and/or method comprisesadministering the active agent(s) (according to any of the respectiveembodiments described herein) prior to and/or subsequent to denervation(according to any of the respective embodiments described herein).

In some embodiments of any of the embodiments described herein relatingto a treatment and/or method, the treatment and/or method comprisesadministering a therapeutically effective amount (as defined herein) ofthe therapeutically active agent (according to any of the respectiveembodiments described herein).

In some embodiments of any of the embodiments described herein relatingto a treatment and/or method, the treatment and/or method comprisesadministering a sub-therapeutically effective amount (as defined herein)of the therapeutically active agent (according to any of the respectiveembodiments described herein), for example, subsequently to denervation(according to any of the respective embodiments described herein).

According to an aspect of some embodiments of the invention, there isprovided a method of treating pulmonary arterial hypertension in asubject in need thereof, the method comprising: a) effecting pulmonaryartery denervation; and b) administering to the subject at least onetherapeutically active agent usable in treating pulmonary arterialhypertension, wherein the administering is at a sub-therapeuticallyeffective amount (of the therapeutically active agent) and/or for a timeperiod shorter than otherwise.

According to an aspect of some embodiments of the invention, there isprovided a use of a device configured for effecting pulmonary arterydenervation (e.g., according to any of the respective embodimentsdescribed herein) in the treatment of pulmonary arterial hypertension(PAH) in a subject in need thereof, wherein the treatment comprisesadministering to the subject at least one therapeutically active agentusable in the treatment of PAH (e.g., according to any of the respectiveembodiments described herein) at a sub-therapeutically effective amountand/or for a time period shorter than otherwise, and effecting pulmonaryartery denervation in the subject.

Herein, the phrase “sub-therapeutically effective amount” refers to adosage which is lower than a dosage (or dosage range) which is atherapeutically effective amount (as defined herein) in the absence oftreatment by denervation.

The term “therapeutically effective amount” denotes a dosage of anactive agent or a composition comprising the active agent that willprovide the therapeutic effect for which the active agent is indicated,herein, treating pulmonary arterial hypertension (e.g., extending a lifeexpectancy of subjects afflicted by pulmonary arterial hypertension).

In some embodiments of any of the embodiments described herein,according to any of the aspects described herein, a treatment and/ormethod comprises administering a sub-therapeutically effective amount(as defined herein) of an active agent subsequently to denervation, andadministering a therapeutically effective amount (as defined herein) ofthe active agent prior to denervation (optionally only prior todenervation).

In some embodiments of any of the respective embodiments describedherein, a sub-therapeutically effective amount is at least 25% lowerthan a therapeutically effective amount (e.g., the lower bound of arange of therapeutically effective amounts). In some such embodiments,the sub-therapeutically effective amount is at least 50% lower than atherapeutically effective amount.

Herein, the phrase “time period shorter than otherwise” refers to aduration of administration of an active agent which is shorter than aduration of administration of the active agent in the absence oftreatment by denervation. Such a “shorter” time period may relate, forexample, to cessation of administration (in a subject treated bydenervation) at a time point during which administration would becontinued in a subject not treated by denervation.

In some embodiments of any of the respective embodiments describedherein, the subject is treated with at least two therapeutically activeagents (according to any of the respective embodiments describedherein), and the method comprises ceasing administration of at least onetherapeutically active agent (such that administration of such an agentis for a time period shorter than otherwise) and continuingadministration of at least one other therapeutically active agent (at atherapeutically effective amount and/or a sub-therapeutically effectiveamount, according to any of the respective embodiments describedherein). In some such embodiments, ceasing administration of at leastone therapeutically active agent is effected subsequent to denervation;optionally immediately subsequent to denervation (i.e., wherein theagent is not administered after denervation).

In some embodiments of any of the embodiments described herein relatingto a treatment and/or method, the treatment and/or method comprisesadministering the active agent(s) (according to any of the respectiveembodiments described herein) prior to denervation (according to any ofthe respective embodiments described herein), and is devoid ofadministering the active agent for a time period of at least one monthsubsequent to the denervation (no agent is administered until after atleast one month has elapsed from denervation). In some embodiments, thetreatment and/or method is devoid of administering the active agent fora time period of at least three months subsequent to the denervation. Insome embodiments, the treatment and/or method is devoid of administeringthe active agent for a time period of at least six months subsequent tothe denervation. In some embodiments, the treatment and/or method isdevoid of administering the active agent for a time period of at leastone year subsequent to the denervation.

According to an aspect of some embodiments of the invention, there isprovided a method of treating pulmonary arterial hypertension in asubject in need thereof, the method comprising effecting pulmonaryartery denervation (according to any of the respective embodimentsdescribed herein) in the subject, the method being devoid ofadministering to the subject a therapeutically active agent usable inthe treatment of PAH (according to any of the respective embodimentsdescribed herein) for a time period of at least one month subsequent tothe denervation (no agent is administered until after at least one monthhas elapsed from denervation). In some embodiments, the method is devoidof administering the active agent for a time period of at least threemonths subsequent to the denervation. In some embodiments, the method isdevoid of administering the active agent for a time period of at leastsix months subsequent to the denervation. In some embodiments, themethod is devoid of administering the active agent for a time period ofat least one year subsequent to the denervation.

Denervation may optionally be effected in a selected population ofsubjects, for example, based on observed correlations betweenresponsiveness to active agents and responsiveness to denervation.

In some embodiments of any of the respective embodiments describedherein, denervation is effected in a subject selected as beingresponsive to one or more therapeutically active agent.

In some embodiments of any of the respective embodiments describedherein, the treatment comprises determining a responsiveness of thesubject to one or more therapeutically active agent (according to any ofthe respective embodiments described herein).

In some embodiments of any of the respective embodiments describedherein, the treatment comprises administering to a subject one or moretherapeutically active agent (according to any of the respectiveembodiments described herein) during a first time period; determining aresponsiveness of the subject to one or more therapeutically activeagent (according to any of the respective embodiments described herein)administered during the first time period; and effecting denervation ina subject determined as being responsive to one or more therapeuticallyactive agent administered during the first time period. In some suchembodiments, the treatment is further characterized in that during asecond time period subsequent to denervation, the treatment furthercomprises administering a sub-therapeutically effective amount of atherapeutically active agent (according to any of the embodimentsdescribed herein relating to a sub-therapeutically effective amount)and/or the treatment is devoid of administering a therapeutically activeagent. In some embodiments, the second time period is at least one month(optionally at least one year) subsequent to the denervation (accordingto any of the respective embodiments described herein.

According to an aspect of some embodiments of the invention, there isprovided a method of treating PAH in a subject in need thereof, themethod comprising determining a responsiveness of the subject to one ormore therapeutically active agent usable in treating PAH (according toany of the respective embodiments described herein). The method furthercomprises effecting pulmonary artery denervation (e.g., according to anyof the embodiments described herein) in a subject responsive to thetherapeutically active agent(s).

Responsiveness of a subject to a therapeutically active agent may bedetermined according to any suitable technique and/or criterion known inthe art, for example, as described in the 2015 European Society ofCardiology (ESC)/European Respiratory Society (ERS)

Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension[Galie et al., Eur Heart J 2016, 37:67-119], the contents of which areincorporated herein by reference, especially contents regardingdetermining responsiveness (or lack thereof) of a treatment for PAH.

In some embodiments of any of the respective embodiments describedherein, according to any of the aspects described herein, a subjectresponsive to a therapeutically active agent (e.g., as determinedaccording to any of the respective embodiments described herein)achieves and/or maintains, upon treatment with the therapeuticallyactive agent, at least one of the following features:

WHO functional class I or II (as defined in the art);

absence of progression of symptoms and clinical signs of right heartfailure;

absence of syncope;

a six-minute walking distance (as defined and determined in the art) ofover 440 meters; a peak VO₂—a.k.a. maximal oxygen consumption—(asdetermined by cardiopulmonary exercise testing) of over 15 ml per minuteper kg and/or over 65% of the predicted peak VO₂ (e.g., according tosex, weight and/or height);

a VE/VCO₂ (ventilatory equivalents for CO₂) slope of less than 36;

BNP (brain natriuretic peptide) plasma levels of less than 50 ng/liter;

NT-proBNP (N-terminal prohormone of BNP) plasma levels of less than 300ng/liter;

A right atrium (RA) area of less than 18 cm² with no pericardialeffusion (as determined by echocardiography and/or cardiac magneticresonance imaging);

a right atrial pressure (RAP) of less than 8 mmHg;

a cardiac index (CI) (as defined in the art) of at least 2.5 liters perminute per meter²; and/or

a mixed venous oxygen saturation (SvO₂) of over 65%.

Denervation:

Pulmonary artery denervation in the context of any of the embodimentsdescribed herein may optionally be effected according to any suitabledenervation technique known in the art.

Herein and in the art, the term “denervation” refers to deprivation ofan organ or body (e.g., an artery) from at least a portion of nervesupply, for example, by damaging and/or killing nerve cells.

Herein throughout, the phrase “pulmonary artery denervation” refers todenervation (as defined herein) of any one or more arteries in thepulmonary circulation system, including large arteries (e.g., the mainpulmonary artery, including the right and left pulmonary arteries),small arteries, and arterioles.

In some embodiments of any of the embodiments described herein,pulmonary artery denervation comprises reducing nerve supply topulmonary small arteries and/or arterioles.

In some embodiments of any of the embodiments described herein,pulmonary artery denervation comprises reducing sympathetic nerve supplyto at least one artery in the pulmonary circulation system, for example,by damaging and/or killing sympathetic nerve cells innervating theartery. In some embodiments, pulmonary artery denervation comprisesreducing sympathetic nerve supply to pulmonary small arteries and/orarterioles, for example, by damaging and/or killing sympathetic nervecells innervating the small arteries and/or arterioles.

In some embodiments of any of the embodiments described herein,denervation comprises damaging nerve tissue (optionally killing nervecells therein) in proximity to a main pulmonary artery. In some suchembodiments, denervation is effected using a device (e.g., a catheterdevice) introduced into the main pulmonary artery (e.g., according toany of the respective embodiments described herein).

Herein, the phrase “main pulmonary artery” encompasses the pulmonaryartery trunk, the right pulmonary artery (i.e., the right branch of themain pulmonary artery), and/or the left pulmonary artery (i.e., the leftbranch of the main pulmonary artery), including the bifurcation area ofthe pulmonary artery trunk.

It is to be appreciated that an artery deprived of nerve supply upondenervation is not necessarily an artery in proximity to nerve tissuedamaged upon denervation. For example, damage to nerve tissue inproximity to a pulmonary artery trunk, right pulmonary artery, and/orleft pulmonary artery may effect denervation of one or more smallarteries and/or arterioles of the pulmonary circulation, which receivenerve supply from nerve cells which pass through a region in proximityto the pulmonary artery trunk, right pulmonary artery, and/or leftpulmonary artery.

Denervation according to any one of the embodiments described herein mayoptionally be effected according to a technique described inInternational Patent Application Publication WO2016/084081, in Chen etal. [J Am Coll Cardiol 2013, 62:1092-1100], and/or in U.S. PatentApplication Publication No. 2013/0204068; the contents of each of whichare incorporated herein by reference in their entirety, and especiallycontents describing techniques for effecting denervation, and moreespecially contents describing denervation by emitting energy (e.g.,ultrasound and/or electromagnetic radiation), for example, in accordancewith any of the embodiments specifically described herein.

In some embodiments of any of the embodiments described herein,effecting denervation comprises thermally damaging nerve tissuesurrounding the main pulmonary artery. Thermally damaging nerve tissuemay optionally be effected by emitting energy (e.g., thereby heating thenerve tissue to a high temperature associated with tissue damage) and/orby cryotherapy (e.g., thereby cooling the nerve tissue to a lowtemperature associated with tissue damage).

In some embodiments of any of the embodiments described herein,effecting denervation by cryotherapy comprises introducing a catheterdevice into a main pulmonary artery lumen, wherein the catheter isconfigured to contain a low-temperature object.

In some embodiments of any of the embodiments described herein,effecting denervation comprises emitting energy from at least oneenergy-emitting device introduced into the body, for example, byintroducing a catheter device comprising the energy-emitting device(s)into a main pulmonary artery lumen. The energy-emitting device(s) mayoptionally comprise a transmitter and/or a transceiver (e.g., anultrasound transmitter and/or transceiver, and/or a radiofrequencytransmitter and/or transceiver).

Emitted energy utilized for denervation (e.g., by thermally damagingnerve tissue) according to any of the respective embodiments describedherein may optionally be ultrasound energy and/or electromagneticradiation. Unfocused ultrasound energy is a non-limiting example of asuitable form of emitted ultrasound energy. Examples of suitable formsof emitted electromagnetic radiation include, without limitation,radiofrequency (RF) energy (monopolar or bipolar); microwave radiation;and ultraviolet, visible and/or infrared radiation (including, forexample, phototherapy).

Additionally or alternatively, other forms of energy suitable tothermally damage nerve tissue are applied, such as plasma, mechanicalmanipulation, kinetic, nuclear, magnetic, electrical, potential, elasticmechanical, chemical and hydrodynamic energy.

In some embodiments, energy having parameters (e.g., intensity,frequency, beam shape, duration and/or other parameters) suitable tothermally damage nerve tissue is emitted. In some embodiments,parameters of the applied energy are selected in accordance with theanatomical treatment location, based on the type(s) and/or quantityand/or distribution of tissue that exist within the targeted volume.Optionally, selective treatment is performed, in which only a part ofthe tissue and/or a certain type of tissue within the target volume suchas nerve tissue is affected by the emitted energy, while other tissueremains substantially unharmed. In an example, the applied energyparameters are selected to produce a temperature profile in the targettissue which thermally damages nerve tissue, but does not have asubstantial effect (e.g., necrosis, denaturation) on non-targeted tissuewithin the target volume.

In some embodiments of any of the embodiments described herein,denervation of nerve tissue is effected within a predefined distancewindow from the main pulmonary artery wall. In some embodiments, thedistance ranges between, for example, from 0.2 to 20 mm, 0.2 to 10 mm, 4to 9 mm, 1 to 6 mm, or any intermediate, larger or smaller distanceranges relative to the intimal aspect of the artery wall. In someembodiments, a position of an energy-emitting devices (e.g.,transceiver) and/or a catheter (according to any of the respectiveembodiments described herein) along the artery, and suitable energyparameters, are selected together in order to target nerve tissue withinthe predefined distance window. In some embodiments, one or moreenergy-emitting devices (e.g., transceivers), optionally of a catheteraccording to any of the respective embodiments described herein, arepositioned within the main pulmonary artery (left pulmonary artery,right pulmonary artery and/or pulmonary artery trunk) within a limitedarea, in which the first bifurcation of the right pulmonary artery setsa border line and a first bifurcation of the left pulmonary artery setsa second border line. In some embodiments, an angiogram and/or CTand/MRI images acquired before and/or during treatment are used fordetermining border line locations.

In some embodiments, the energy-emitting device(s) (e.g.,transceiver(s)) are positioned such that a tissue volume covered by thebeam of emitted energy encompasses mostly nerves innervating one or morearteries of the pulmonary circulation. Optionally, the volume isselected such that nerves innervating other organs are avoided or theirpresence is insignificant. Optionally, at least 25%, at least 50%, atleast 60%, at least 70%, at least 80% by volume of nerve tissue withinthe tissue volume covered by the beam includes sympathetic nerves, orintermediate, higher or lower volume of nerve tissue.

In some embodiments, energy parameters are selected using acomputational model that takes into account one or more of metabolicheat generation in tissue, heat absorption characteristics of thetissue, heat conductivity, metabolic flow in the tissue, tissue density,acoustic absorption, volumetric blood perfusion in the tissue, cellsensitivity to heat, cell sensitivity to mechanical or acoustical damageand/or other tissue parameters. In some embodiments, the model isconstructed according to a finite element analysis which assists indetermining a temperature distribution profile in the tissue, in spaceand/or time. Optionally, the finite element analysis takes into accounta solution of the bioheat equation under selected conditions.

In some embodiments, the energy parameters are selected so that energydeposited in the tissue outside the artery is sufficient to thermallydamage nerves within the distance window. In some embodiments, theemitted beam is selective in the sense that nerve tissue within the beamcoverage is thermally damaged, while other, non-target tissue within thebeam coverage (such as adipose tissue, lymph and/or other non-targettissue) remains substantially undamaged. In some embodiments, the tissuespecific damage has a higher affinity to nerve tissue surrounded byfatty tissue, due to the low heat conductivity of the fatty tissue.Optionally, due to acoustic absorption and/or thermal sensitivityproperties that are higher than acoustic absorption and/or thermalsensitivity properties of other tissue, such as lymph tissue, fibroustissue, or connective tissue, the acoustic energy affects the nervetissue most.

In some embodiments, cooling as a result of blood flow through the mainpulmonary artery and/or cooling as a result of perfusion in the tissuereduces or prevents thermal damage to the intima and media layers of theartery wall, so that a significant thermal effect starts only at adistance away from the wall.

In some embodiments of any of the respective embodiments describedherein, denervation comprises reducing thermal damage to the mainpulmonary artery wall by taking advantage of a streaming effect producedin response to emission of ultrasound. In some embodiments, ultrasoundemitted at a frequency of 8-13 MHz, 5-10 MHz, 10-20 MHz or intermediate,higher or lower frequency ranges and an intensity of from 20-100 W/cm²,30-70 W/cm², 35-65 W/cm², or intermediate, higher or lower intensityranges produces fluid circulation in which fluid is caused to flow fromthe energy-emitting device surface towards the artery wall, therebydissipating heat away from the ultrasound-emitting device (e.g.,transceiver) and, in turn, from the artery wall. In some embodiments,even if fluid (e.g. blood) in the artery is static or the flow isreduced (e.g. due to pulsation, such as during diastole) the acousticstreaming effect produced by emission of ultrasound energy sufficientlycools the artery wall, preventing at least the intima and media of theartery wall from thermal damage. In some embodiments, cooling providedby the streaming effect is sufficient to dissipate at least 10%, atleast 20%, at least 40% or intermediate, higher or lower percentage ofthe power of the emitted energy. In some embodiments, cooling providedby the streaming effect is sufficient to reduce a temperature of theintima to a temperature of 42° C. or lower.

In some embodiments of any of the embodiments described herein,denervation is performed at a plurality of locations situated along along axis of the main pulmonary artery (left pulmonary artery, rightpulmonary artery and/or pulmonary artery trunk), for example, from 2 to8 locations within each of the left, right and main artery. According tosome exemplary embodiments, denervation is performed at from 6 to 16treatment locations, for example 6, 7, 8, 10, 12, 14 or any smaller orlarger number of treatment locations within the pulmonary arteries. Insome embodiments, the number of treatment locations within the pulmonaryarteries is selected based on the anatomy of one or more of thepulmonary arteries and/or the distance from a selected nerve. In someembodiments, the number of treatment locations is selected based on thesize of the “working frame”, as described herein.

Optionally, a distance between adjacent treatment locations ranges from0.1 to 2 cm, from 0.5 to 1 cm, from 1 to 2 cm, or intermediate, longeror shorter distances. In some embodiments, energy is emitted atplurality of locations to damage a nerve (or a bundle of nerves) at aplurality of sections along the length of the nerve. For example, anerve may be damaged at an initial section of the axon and at a distalsection of the axon (e.g., at or near the synapse), impairing also anintermediate section of the axon as a result. In some embodiments, theextent of thermal damage is high enough to prevent the nerve fromreconnecting and/or regenerating for at least a time period followingtreatment (for example at least 1 month, 3 months, 6 months, 1 yearfollowing treatment). In some embodiments, nerve portions thattransport, store and/or produce neurotransmitters are damaged.

In some embodiments, the catheter used for delivering the denervationhas a length in a range of 80-200 cm, for example 80 cm, 100 cm, 120 cmor any intermediate, smaller or larger value.

According to some embodiments, denervation is effected for a duration ina range of 10-40 minutes, for example 15 minutes, 20 minutes, 25minutes, 30 minutes or any intermediate, smaller or larger timeduration. In some embodiments, the treatment duration is determinedbased on the number of selected treatment sites. Alternatively oradditionally, the treatment duration is determined based on the distancebetween the treated nerve and the one or more treatment locations withinthe pulmonary arteries. Optionally, the treatment duration is determinedbased on the treatment protocol or parameters thereof.

In some embodiments of any of the respective embodiments describedherein, thermal damage is manifested as coagulation, vacuolation and/ornuclei pyknosis of the targeted nerve. In some embodiments, the thermaldamage results in tissue fibrosis and optionally in formation ofremodeled scar tissue.

In some embodiments, a temperature distribution profile of the thermaldamage produced depends on tissue homogeneity. Optionally, in homogenoustissue, a cross section profile of thermal damage takes the form of ateardrop.

In some embodiments of any of the respective embodiments describedherein, denervation comprises thermally damaging nerve tissue (e.g., byemitting energy according to any of the respective embodiments describedherein) without causing substantial damage to the artery wall.Optionally, damage to the wall is reduced by keeping the energy-emittingdevice(s) (e.g., ultrasound-emitting device(s)) according to any of therespective embodiments described herein away from the wall, for exampleby using a distancing device. In some embodiments, denervation comprisestreating from an artery in which a wall disorder such as thrombus oratheroma exist, while reducing a risk of breakage of the thrombus oratheroma, which may result in emboli and possibly occlude the artery.

In some embodiments of any of the respective embodiments describedherein, denervation comprises activating one or more energy-emittingdevices (e.g., ultrasound-emitting devices) according to any of therespective embodiments described herein to emit energy towards aselected direction, and/or deactivating one or more energy-emittingdevices (e.g., ultrasound-emitting devices) according to any of therespective embodiments described herein to reduce or prevent emission inone or more other directions.

In some embodiments of any of the respective embodiments describedherein, thermally damaging nerve tissue associated with a pulmonaryartery (e.g., a main pulmonary artery) comprises selectively damagingnerves that are not coated by myelin, for example, by subjecting thenerve tissue to a temperature at which nerves that are not coated bymyelin are selectively damaged, optionally a temperature in a range offrom 47° C. to 57° C. In some embodiments, selective damage of nervetissue is effected by emitting energy (e.g., according to any of theembodiments described herein) at a frequency, intensity and/or durationsufficient to produce a suitable predetermined temperature profile inthe tissue, for example, in a range of from 47° C. to 57° C. Optionally,upon increasing the temperature, for example, to a range of from 58° C.to 70° C., both non-coated nerves and myelin coated nerves are thermallydamaged.

In some embodiments of any of the respective embodiments describedherein, denervation comprises utilizing a transceiver, optionally anultrasonic transceiver, as an energy-emitting device (according to anyof the respective embodiments described herein), for example, tofacilitate selective treatment of nerve tissue (e.g., causing damage toselected nerves without causing substantial damage to non-targetedtissue, such as surrounding organs and/or other nerve tissue). In someembodiments, denervation comprises using the same transceiver tocharacterize tissue and to emit energy for treating targeted tissue. Insome embodiments, characterizing tissue comprises identifying one ormore organs such as the lungs, trachea, lymph, bronchi or others. Insome embodiments, organs are identified based on their echo signalreflection. Optionally, the reflected signals are received by the one ormore ultrasonic transceivers (e.g., of a catheter device, according toany of the respective embodiments described herein), and are analyzed todetermine the organ type and/or the relative distance of the organ fromthe lumen from which treatment is applied, such as the main pulmonaryartery lumen. In some embodiments, the transceivers (e.g., ultrasonictransceivers) are activated at a first energy profile to identify and/orcharacterize tissue, and at a second energy profile to treat tissue.Optionally, non-targeted tissue is identified. Additionally oralternatively, targeted tissue is identified.

In some embodiments of any of the respective embodiments describedherein, denervation comprises feedback-based treatment of the pulmonaryvasculature. In some embodiments, treatment is continued and/or modifiedbased on one or more measurements of physiological control parameters,including local parameters such as, for example, pulmonary arterydiameter, bronchi diameter, and/or systemic parameters, which may be abyproduct of denervation, including, for example, heart rate,respiratory volume, and/or other physiological parameters. In someembodiments, the physiological parameters are measured internally to thebody. Additionally or alternatively, the physiological parameters aremeasured externally to the body. In some embodiments, a catheter (e.g.,ultrasonic catheter) according to any of the respective embodimentsdescribed herein is configured to acquire the one or more physiologicalparameters. In an example, a physiological parameter such as a diameterof the pulmonary artery is estimated by analyzing echo signals (e.g.,ultrasound echo signals) reflected by the artery walls and received bythe one or more transceivers (e.g., of a catheter device) according toany of the respective embodiments described herein. In some embodiments,the physiological parameter is acquired by stimulating the nervoussystem to evoke an observable physiological response and/or a chain ofresponses, one or more of which are detectable and optionallymeasureable.

In some embodiments, a measurement of the physiological parameteracquired before denervation treatment is compared to a measurement ofthe same physiological parameter following treatment, to determinetreatment effectiveness. For example, an increase in artery diameterabove a certain threshold, measured following treatment, may indicatethat the treatment was effective.

In some embodiments, immediate feedback is provided, and denervationtreatment is modified and/or ceased based on the feedback. In anexample, immediate feedback comprises assessing dilation of the bronchi,which may be observed shortly after denervation. In another example,immediate feedback comprises assessing arterial blood pressure.

In some embodiments of any of the respective embodiments describedherein, a catheter device (according to any of the respectiveembodiments described herein) introduced to a subject's body is suitablefor reducing unwanted movement of the catheter, and more specificallymovement of at least a distal portion of the catheter when a moreproximal portion of the catheter is passed through cardiac vasculature,where it is subjected to movement resulting from heart pulsation. Insome embodiments, the catheter is passed through the right ventricle ofthe heart. In some cases, contraction of the ventricle may causemovement of the catheter shaft, thereby possibly moving the distal headof the catheter, which comprises one or more energy-emitting devicesaccording to any of the respective embodiments described herein).

In some embodiments, a structure of the catheter shaft is selected todamp movement resulting from heart pulsation, potentially reducing anumber of movements and/or a range of movement of at least a distal headof the catheter. In some embodiments, one or more locations along thecatheter shaft are structured to provide a full or partial axialdecoupling between axial segments of the catheter, for example so thatmovement of the head at a distal end of the device is least affected bymovement of a more proximal portion of the catheter shaft. Additionallyor alternatively, the catheter is anchored to a certain location in theartery and/or to other tissue or organs, to prevent or reduce movementof the catheter relative to the tissue, for example during emission ofenergy, for example, ultrasound. Optionally, a small range of movementis permitted, such as movement to an extent which does not affecttargeting. Additionally or alternatively, a “working frame” is provided,and the catheter is maneuvered within the working frame. Additionally oralternatively, movement of the catheter is synchronized with movement ofthe targeted tissue, for example by anchoring the catheter to astructure that moves in a similar pattern to the targeted tissue.

In some embodiments, at least a head of the catheter, comprising the oneor more energy-emitting devices according to any of the respectiveembodiments described herein (ultrasound-emitting device(s)) ispositioned and/or oriented within the lumen from which denervationtreatment is applied at a predetermined location. Optionally,positioning of the catheter and/or directing of an energy (e.g.,ultrasound) beam is selected based on one or more of: a distance fromthe tissue to be treated, a distance from the lumen wall, a positionalong the length of the lumen, parameters of the beam emitted by theenergy-emitting devices (e.g., beam shape), and/or others. In someembodiments, positioning of the catheter and/or directing of the beam isperformed by delivering the catheter over a pre-shaped guide wire, forexample a spiral guide wire or a guide wire curved to a substantial Zshape. A potential advantage of the spiral configuration may includesetting an advancement path for the catheter in which at any point alongthe path, at least the catheter head is maintained at a selecteddistance from the lumen wall, for example in proximity to the lumenwall. Optionally, the catheter is positioned a distance between 0.1 mmto 20 mm from the lumen wall. Optionally, the distance is selected inaccordance with the intensity applied, for example a distance rangingfrom 0.1 mm to 5 mm, 5 mm to 10 mm, 15 mm to 20 mm or intermediate,larger or smaller distance ranges are used with an intensity between 20W/cm² to 80 W/cm². In some embodiments, the spiral diameter (i.e. adiameter of a loop) is selected according to the lumen diameter.Additionally or alternatively, the spiral diameter is selected accordingto the catheter diameter, for example a diameter of the catheter head.In some embodiments, a similar effect to delivering the catheter over ahelical structure may be obtained by delivering the catheter over theZ-shaped wire, and rotating the wire. Optionally, the catheter isintroduced over the wire to a position in which the catheter head isproximal to the curved portion of the wire. Alternatively, the catheteris introduced over the wire to a position in which the catheter head isdistal to the curved portion of the wire. Another potential advantage ofthe spiral and/or Z-shaped configurations (and/or any otherconfigurations suitable to position the catheter away from the center ofthe lumen and in proximity to the walls) may include facilitatingtreating the lumen circumferentially. Optionally, when applyingcircumferential treatment by delivering the catheter over a curved guidewire, the curvature of the wire can be selected to obtain a certainorientation of the energy-emitting device(s) at the head of thecatheter, for example positioning an energy-emitting device such that alonger dimension of the energy-emitting device (for example being arectangular energy-emitting device) extends at an angle relative to alongitudinal axis of the lumen.

In some embodiments of any of the embodiments described herein,denervation relates to a selected target tissue volume. In someembodiments, denervation relates to an anatomical treatment zone forpositioning an energy-emitting device according to any of the respectiveembodiments described herein (optionally an ultrasonic transceiver),optionally of a catheter according to any of the respective embodimentsdescribed herein, such that the emitting device is positioned to treatthe aforementioned selected target tissue volume, while damage tonon-targeted tissue types and/or non-targeted organs is reduced.

In some embodiments, the selected treatment zone (for denervation)provides for targeting a tissue volume comprising a high nerve contentas compared to other tissue volumes, while reducing a risk of damage tonon-targeted tissue (such as adipose tissue, connective tissue) and/orto nearby organs (such as the aorta, vagus, esophagus and/or otherorgans). A potential advantage of positioning an energy-emitting deviceand/or catheter at the selected treatment zone may include optimizing atradeoff between denervation efficacy and treatment safety, such asavoiding damage to non-targeted tissue. Other optimization methods caninclude treating the most efficient treatment location. It was found tobe the most efficient due to highest nerve density, and it is also, asafe location to treat.

In some embodiments, the anatomical treatment zone (for denervation)comprises an ostial and/or near-ostial area within the lumen of the leftpulmonary artery, in the vicinity of the bifurcation in which the mainpulmonary trunk splits into the left pulmonary artery and the rightpulmonary artery. In some embodiments, the anatomical treatment zone islocated at a distance of less than 50 mm, 40 mm, 30 mm, less than 20 mm,less than 10 mm, or intermediate, longer or shorter distances from acentral longitudinal axis of the main trunk of the pulmonary artery.Additionally or alternatively, the anatomical treatment zone is situatedat an axial distance (measured along the length of the left pulmonaryartery) from 5 to 50 mm, 0 to 10 mm, 10 to 30 mm or intermediate, longeror shorter distance ranges from the artery ostium. Additionally oralternatively, the anatomical treatment zone is situated at a distanceof less than 10 mm, less than 7 mm, less than 3 mm from the point ofmaximal curvature of the left pulmonary artery. Additionally oralternatively, the anatomical treatment zone is situated within therange of the first 1/5, 1/4, 1/3 or intermediate, longer or shortersections of the total length of the left pulmonary artery, measured forexample between the long axis of the main pulmonary trunk to the lateralbifurcation of the left pulmonary artery, where it splits into two ormore branches, each extending towards one of the lobes of the left lung.

The “ostium” refers herein to the bifurcation point that is mutual tothe main trunk, the left and the right pulmonary arteries.

In some embodiments the ostium point is first located by fluoroscopyprior to deciding the treatment zone for denervation.

In some embodiments, the anatomical treatment zone (for denervation)does not include the right pulmonary artery. A potential advantage ofnot treating from within the right pulmonary artery may include reducingpotential damage (e.g. thermal damage) to the aorta, which ascends withthe main pulmonary trunk and arches around the right pulmonary artery,and/or to reduce potential damage to the vagus nerve, which extendsdorsally to the right pulmonary artery. Alternatively, the anatomicaltreatment zone comprises the right pulmonary artery.

In some embodiments, treatment for denervation (according to any of therespective embodiments described herein) is applied from the anatomicaltreatment zone to treat a selected target tissue volume. In someembodiments, the selected target tissue volume comprises one or morenerve plexuses situated to the left of the left pulmonary artery. Insome embodiments, the selected target tissue volume is locatedlaterally, posteriorly and/or anteriorly to the left pulmonary artery.In some embodiments, the selected target tissue volume is located withina distance range of 0.2-30 mm from a point of maximal curvature of theleft pulmonary artery. Additionally or alternatively, the selectedtarget tissue volume is located laterally to the main trunk of thepulmonary artery, inferior to the left pulmonary artery.

In some embodiments, energy is emitted towards a circumferential regionof the left pulmonary artery. Optionally, the one or moreenergy-emitting devices (optionally ultrasound-emitting devices, e.g.,transceivers) are activated and/or rotated during and/or betweentreatment sessions to cover different circumferential sections. In someembodiments, a line of energy-emitting devices (e.g., electrodes,ultrasonic transceivers) are aligned along the circumference of theartery and only the ones facing to target zone are activated. This maybe potentially advantages to increasing safety.

In some embodiments, when emitting energy from the selected anatomicaltreatment zone towards the selected target tissue volume, a separationangle of at least 20 degrees, at least 30 degrees, at least 60 degreesor intermediate, larger or smaller angle is formed between the emittedenergy beam and non-targeted organs. A potential advantage of emittingenergy such that a separation angle is formed between the non-targetedorgans and the emitted beam may include increasing treatment safety, aseven if the beam is emitted at an offset angle from the selected angle,at least to some extent, non-targeted tissue will remain substantiallyunharmed.

In some embodiments, a structure of the catheter is designed to providefor positioning one or more energy-emitting devices (e.g., ultrasonictransceivers) within the anatomical treatment zone, for example by thecatheter comprising a shaft that is shaped and/or deformable to acurvature that matches the curvature of the left pulmonary artery.

In some embodiments, denervation is effected using a catheter whichexhibits synergy with the anatomy of the selected treatment zone and/orthe anatomy of a delivery path of the catheter. In some embodiments, thephysician utilizes the anatomy to direct the catheter to a selectedtreatment location, such as within the anatomical treatment zonedescribed herein. In some embodiments, the anatomy naturally “assists”in directing the catheter to the selected location, for example bydefining boundaries which force the catheter to the selected location.

In some embodiments, a shaft of the catheter is shaped in a manner inwhich at least some portions of the shaft lean and/or anchor againstwalls of a lumen through which the catheter is introduced to theselected treatment location, for example a lumen of the pulmonary arterytrunk and/or a lumen of the right and/or left pulmonary arteries, toprovide for positioning a head of the catheter at a selected treatmentzone. In an example, the catheter shaft is arched, allowing a moreproximal portion of the shaft to lean against a right wall of thepulmonary artery trunk to thereby position a more distal portion of thecatheter which includes an energy-emitting device (or other device foreffecting denervation) within a treatment zone located in the ostialleft pulmonary artery section.

In some embodiments, a path through which an energy-emitting deviceand/or catheter is introduced to the treatment zone follows the naturalpath of blood flow. Optionally, the flow of blood assists in directingthe energy-emitting device and/or catheter to the selected treatmentlocation, for example by using an inflatable balloon tip and/or sail tipproviding for flow-directed flotation of the energy-emitting deviceand/or catheter to the selected location.

In some embodiments of any of the embodiments described herein,denervation relates to targeting nerves according to mapping of thenerves. In some embodiments, nerves are selected as target according toone or both of a distance of the nerve from the artery lumen and a crosssectional area of the nerve. In some embodiments, a number of targetnerves is selected to reduce one or more of: mPAP (mean pulmonaryarterial pressure), pulmonary vascular resistance, contractibility,and/or systemic pressure levels in the pulmonary artery as compared tomPAP levels measured before treatment. In some embodiments, right heartejection fraction is increased. Generally, the number of target nervesmay be selected to improve (e.g. increase or decrease a level of) anyparameter associated with pulmonary hypertension.

In some embodiments of any of the embodiments described herein, acatheter structure and/or a denervation protocol are selected based onan anatomy of the pulmonary artery region in which the catheter isintended to be positioned during treatment. For example, whenpositioning a catheter in the pulmonary artery trunk, in which the crosssectional area is relatively large (comprising a diameter which is about1.5 times a diameter of the right or left pulmonary arteries), it may bedesirable to position the catheter head closer to the lumen wall ascompared to, for example, when treating in an artery region of smallercross sectional area. Optionally, when treating an artery region havinga relatively large cross sectional area, higher intensities are applied.In some embodiments, a high intensity is applied to compensate forundesired movement of the catheter within the large artery region.Optionally, by directing energy at a high intensity towards a largevolume or cross section of tissue, the energy spreads over the largevolume, thereby reducing the actual intensity of energy that effectivelyreaches the various tissue locations within the large volume.

In some embodiments of any of the embodiments described herein,denervation is effected (e.g., by selecting suitable parameters ofenergy emission) so as to reduce one or more of the followingparameters: right atrial pressure (RAP), right ventricle pressures(RVP), systolic pulmonary artery pressure (sPAP), mean pulmonary arterypressures (mPAP), pulmonary vascular resistance (PVR), and/or NT-pro-BNPlevels (e.g., as exemplified herein).

In some embodiments of any of the embodiments described herein,denervation is effected (e.g., by selecting suitable parameters ofenergy emission) so as to increase one or more of the followingparameters: cardiac output (CO), cardiac index (CI), ejection fraction(EF), pulmonary distensability, pulmonary compliance, pulmonarystiffness, exercise tolerance—6 minutes walking distance (6MWD), qualityof life (as assessed by questionnaire, e.g., emPHasis questionnaire),cardiopulmonary exercise testing and/or peak VO2 (e.g., as exemplifiedherein).

RAP, RVP, sPAP, mPAP, PVR, NT-pro-BNP levels, cardiac output, cardiacindex, ejection fraction, pulmonary distensability, pulmonarycompliance, pulmonary stiffness, exercise tolerance—6 minutes walkingdistance (6MWD), cardiopulmonary exercise testing and/or peak VO2 may bedetermined using any suitable technique, procedure, and/or apparatusknown in the art (e.g., for cardiac MRI and/or echocardiography),optionally as described below in the Examples section herein and/orFIGS. 1 and/or 2.

Formulation:

The therapeutically active agent(s) of any of the embodiments of theinvention described herein can be administered to a subject per se, orin a pharmaceutical composition where it is mixed with suitable carriersor excipients.

As used herein a “pharmaceutical composition” refers to a preparation ofone or more of the active agents described herein with other chemicalcomponents such as physiologically suitable carriers and excipients. Thepurpose of a pharmaceutical composition is to facilitate administrationof a compound to an organism.

Hereinafter, the phrases “physiologically acceptable carrier” and“pharmaceutically acceptable carrier” which may be interchangeably usedrefer to a carrier or a diluent that does not cause significantirritation to an organism and does not abrogate the biological activityand properties of the administered compound. An adjuvant is includedunder these phrases.

Herein the term “excipient” refers to an inert substance added to apharmaceutical composition to further facilitate administration of anactive agent. Examples, without limitation, of excipients includecalcium carbonate, calcium phosphate, various sugars and types ofstarch, cellulose derivatives, gelatin, vegetable oils and polyethyleneglycols.

Techniques for formulation and administration of drugs may be found in“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition, which is incorporated herein by reference.

Suitable routes of administration may, for example, include oral,rectal, transmucosal, especially transnasal, intestinal or parenteraldelivery, including intramuscular, subcutaneous and intramedullaryinjections as well as intrathecal, direct intraventricular,intracardiac, e.g., into the right or left ventricular cavity, into thecommon coronary artery, intravenous, intraperitoneal, intranasal, orintraocular injections.

Optionally, one may administer the pharmaceutical composition in a localrather than systemic manner, for example, via injection of thepharmaceutical composition directly into a tissue region (e.g., regionof the vasculature) of a patient.

The term “tissue” refers to part of an organism consisting of cellsdesigned to perform a function or functions. Examples include, but arenot limited to, brain tissue, retina, skin tissue, hepatic tissue,pancreatic tissue, bone, cartilage, connective tissue, blood tissue,muscle tissue, cardiac tissue brain tissue, vascular tissue, renaltissue, pulmonary tissue, gonadal tissue, hematopoietic tissue.

Pharmaceutical compositions of some embodiments of the invention may bemanufactured by processes well known in the art, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with some embodimentsof the invention thus may be formulated in conventional manner using oneor more physiologically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active agents intopreparations which, can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the active agents the pharmaceutical composition may beformulated in aqueous solutions, preferably in physiologicallycompatible buffers such as Hank's solution, Ringer's solution, orphysiological salt buffer. For transmucosal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art.

For oral administration, the pharmaceutical composition can beformulated readily by combining the active compounds withpharmaceutically acceptable carriers well known in the art. Suchcarriers enable the pharmaceutical composition to be formulated astablets, pills, dragees, capsules, liquids, gels, syrups, slurries,suspensions, and the like, for oral ingestion by a patient.Pharmacological preparations for oral use can be made using a solidexcipient, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose; and/or physiologically acceptable polymers suchas polyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as cross-linked polyvinylpyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fitcapsules made of gelatin as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active agents in admixture with filler such aslactose, binders such as starches, lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In soft capsules, the activeagents may be dissolved or suspended in suitable liquids, such as fattyoils, liquid paraffin, or liquid polyethylene glycols. In addition,stabilizers may be added. All formulations for oral administrationshould be in dosages suitable for the chosen route of administration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by nasal inhalation, the active agents for useaccording to some embodiments of the invention are convenientlydelivered in the form of an aerosol spray presentation from apressurized pack or a nebulizer with the use of a suitable propellant,e.g., dichlorodifluoromethane, trichlorofluoromethane,dichloro-tetrafluoroethane or carbon dioxide. In the case of apressurized aerosol, the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of, e.g.,gelatin for use in a dispenser may be formulated containing a powder mixof the compound and a suitable powder base such as lactose or starch.

The pharmaceutical composition described herein may be formulated forparenteral administration, e.g., by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multidose containers with optionally, anadded preservative. The compositions may be suspensions, solutions oremulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of the active preparation in water-soluble form.Additionally, suspensions of the active agents may be prepared asappropriate oily or water based injection suspensions. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acids esters such as ethyl oleate, triglycerides orliposomes. Aqueous injection suspensions may contain substances, whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe active agents to allow for the preparation of highly concentratedsolutions.

Alternatively, the active agent may be in powder form for constitutionwith a suitable vehicle, e.g., sterile, pyrogen-free water basedsolution, before use.

The pharmaceutical composition of some embodiments of the invention mayalso be formulated in rectal compositions such as suppositories orretention enemas, using, e.g., conventional suppository bases such ascocoa butter or other glycerides.

Pharmaceutical compositions suitable for use in context of someembodiments of the invention include compositions wherein the activeagents are contained in an amount effective to achieve the intendedpurpose. More specifically, a therapeutically effective amount means anamount of active agent(s) effective to prevent, alleviate or amelioratepulmonary arterial hypertension (or symptoms associated with pulmonaryarterial hypertension), or prolong the survival of the subject beingtreated.

Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

For any preparation used in the methods of the invention, thetherapeutically effective amount or dose can be estimated initially fromin vitro and cell culture assays. For example, a dose can be formulatedin animal models to achieve a desired concentration or titer. Suchinformation can be used to more accurately determine useful doses inhumans.

Toxicity and therapeutic efficacy of the active agents described hereincan be determined by standard pharmaceutical procedures in vitro, incell cultures or experimental animals. The data obtained from these invitro and cell culture assays and animal studies can be used informulating a range of dosage for use in human. The dosage may varydepending upon the dosage form employed and the route of administrationutilized. The exact formulation, route of administration and dosage canbe chosen by the individual physician in view of the patient'scondition. See e.g., Fingl, et al., 1975, in “The Pharmacological Basisof Therapeutics”, Ch. 1 p.1.

Dosage amount and interval may be adjusted individually to providelevels of the active agent(s) (e.g., in the blood) sufficient to induceor suppress the biological effect (minimal effective concentration,MEC). The MEC will vary for each preparation, but can be estimated fromin vitro data. Dosages necessary to achieve the MEC will depend onindividual characteristics and route of administration. Detection assayscan be used to determine plasma concentrations.

Depending on the severity and responsiveness of the condition to betreated, dosing can be of a single or a plurality of administrations,with course of treatment lasting from several days to several weeks oruntil cure is effected or diminution of the disease state is achieved.

The amount of a composition to be administered will, of course, bedependent on the subject being treated, the severity of the affliction,the manner of administration, the judgment of the prescribing physician,etc.

Compositions according to some embodiments of the invention may, ifdesired, be presented in a pack or dispenser device, such as an FDAapproved kit, which may contain one or more unit dosage forms containingthe active agent(s). The pack may, for example, comprise metal orplastic foil, such as a blister pack. The pack or dispenser device maybe accompanied by instructions for administration. The pack or dispensermay also be accommodated by a notice associated with the container in aform prescribed by a governmental agency regulating the manufacture, useor sale of pharmaceuticals, which notice is reflective of approval bythe agency of the form of the compositions or human or veterinaryadministration. Such notice, for example, may be of labeling approved bythe U.S. Food and Drug Administration for prescription drugs or of anapproved product insert. Compositions comprising a preparation accordingto the invention formulated in a compatible pharmaceutical carrier mayalso be prepared, placed in an appropriate container, and labeled fortreatment of an indicated condition (e.g., in combination with pulmonaryartery denervation), as is further detailed above.

As used herein the term “about” refers to ±20%, wherein in someembodiments of any of the respective embodiments described herein,“about” refers to ±10%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

When reference is made to particular sequence listings, such referenceis to be understood to also encompass sequences that substantiallycorrespond to its complementary sequence as including minor sequencevariations, resulting from, e.g., sequencing errors, cloning errors, orother alterations resulting in base substitution, base deletion or baseaddition, provided that the frequency of such variations is less than 1in 50 nucleotides, alternatively, less than 1 in 100 nucleotides,alternatively, less than 1 in 200 nucleotides, alternatively, less than1 in 500 nucleotides, alternatively, less than 1 in 1000 nucleotides,alternatively, less than 1 in 5,000 nucleotides, alternatively, lessthan 1 in 10,000 nucleotides.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Various embodiments and aspects of the present invention as delineatedhereinabove and as claimed in the claims section below find experimentalsupport in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions illustrate some embodiments of the invention in anon-limiting fashion.

Example 1 Safety and Effect of Denervation of Sympathetic Nerves inCombination with Drug Therapy on Pulmonary Arterial Hypertension

The safety, performance and initial effectiveness of denervation ofsympathetic nerves surrounding the pulmonary vasculature for treatingPAH is evaluated. Denervation is effected using ultrasonic energy,optionally using a Therapeutic Intra-Vascular Ultra-Sound (TIVUS™)system.

Adult patients (e.g., about 15 patients) with idiopathic PAH, PAHassociated with connective tissue disease, anorexigen-induced PAH and/orheritable PAH, are selected, in WHO functional class III (markedlimitation of physical activity, comfortable at rest, less than ordinaryactivity causes undue dyspnoea or fatigue, chest pain or near syncope),with stable PAH on a stable drug regimen (i.e., with no changes of doseor medication for a minimum of 3 months prior to enrollment) of twoPAH-specific medications other than parenteral prostanoids. The patientshave eGFR levels of at least 30 ml per minute per 1.73 m² and/or serumcreatinine levels of less than 150 μM.

PAH diagnosis is optionally confirmed by hemodynamic evaluation, whichshows all of the following: mean pulmonary artery pressure (mPAP) of atleast 25 mmHg at rest; pulmonary capillary wedge pressure (PCWP) or leftventricular end diastolic pressure (LVEDP) of no more than 15 mmHg;pulmonary vascular resistance (PVR) at rest of over 3 Wood units; andnot meeting the criteria for a positive vasodilator response (fall inmPAP of at least 10 mmHg to no more than 40 mmHg).

Patients treated with parenteral prostanoids; patients having animplantable cardiac pacemaker, ICD, neurostimulator or drug infusiondevice; patients who have experienced a recent (e.g., in the previous 6months) myocardial infarction, unstable angina pectoris or acerebrovascular accident patients with a pulmonary artery aneurysm,moderate to severe pulmonary artery stenosis, significant co-morbidconditions and/or short life expectancy (e.g., less than a year);patients with pulmonary artery anatomy that precludes treatment orpatients unable to undergo an MRI scan; and/or women who are pregnant orplanning a pregnancy soon (e.g., within 12 months), are optionallyexcluded from the study.

Safety is determined by evaluating procedural related adverse events(complications) (e.g., up to 30 days post-procedure), includingpulmonary artery perforation/dissection, acute thrombus formation inpulmonary artery, pulmonary artery aneurysm, vascular stenosis,hemoptysis, and/or death (including PAH-related and/or proceduralrelated).

Safety is also optionally determined by evaluating long-term (e.g., upto 12 months post-procedure) procedural related adverse events (asdescribed hereinabove), PAH worsening adverse events and/or death.

Variables which are determined in the course of the study include:

a) Changes from baseline of:

PAH-specific medications (e.g., at 2 weeks, 1 month, 6 months and/or 12months);

Physical examination parameters (e.g., at 2 weeks, 1 month, 6 monthsand/or 12 months);

ECG (electrocardiography) parameters (e.g., at 1 month, 6 months and/or12 months);

6-minute walking distance (6MWD) (e.g., at 1 month and/or 12 months);

Activity monitored using an actigraphy device (e.g., at 6 months and/or12 months);

Arterial vs. venous catecholamine concentration (e.g., at 6 monthsand/or 12 months); and/or

Hemodynamic response to inhaled nitric oxide, including mPAP and PVR(e.g., at 6 months and/or 12 months);

b) Cardiac and pulmonary MRI parameters (e.g., at 1 month);

c) Echocardiography parameters (e.g., at 12 months);

d) Quality of life, as determined by emPHasis questionnaire (e.g., at 12months); and/or

e) Long-term surveillance (e.g., at 2, 3, 4 and/or 5 years) fordetermining survival (or cause of mortality), hospitalization due toPAH, interventional or surgical procedures such as atrial septostomy orlung transplantation, worsening of WHO functional class, and/orescalation of drug therapy.

Elements of a study and optional times thereof are presented in FIG. 1.An optional flow chart for a study is presented in FIG. 2.

Effectiveness of treatment is determined by evaluating changes inhemodynamic changes from baseline (e.g., mPAP, PVR, right atrialpressure and/or cardiac index), change in 6MWD, change in quality oflife, change in right ventricular (RV) function as assessed by MRI(e.g., RV ejection fraction, RV end diastolic and systolic volume, wallthickness, aortic flow, PA flow, and/or main, left and right PAdiameter), change in right ventricular (RV) function/structure asassessed by echocardiography (e.g., tricuspid annular plane systolicexcursion, RV myocardial performance index, RV ejection fraction, and/orRV end diastolic and systolic volume), and/or NT-pro BNP (N-terminalprohormone of brain natriuretic peptide) serum levels (e.g., at 1, 6and/or 12 months).

Effectiveness of denervation in combination with any given drug therapy(e.g., combination of drugs) is optionally observed as improvement ofpatient condition in comparison with what would have been expected inthe absence of denervation, e.g., based on baseline parameters, patienthistory, and/or expected progression of PAH as reported in the art.

Improvement of patient condition is optionally evidenced as a reductionone or more of: right atrial pressure (RAP), right ventricle pressures(RVP), systolic pulmonary artery pressure (sPAP), mean pulmonary arterypressures (mPAP), pulmonary vascular resistance (PVR), and/or NT-pro-BNPlevels and/or

as an increase in one or more of: cardiac output (CO), cardiac index(CI), ejection fraction (EF), pulmonary distensability, exercisetolerance—6 minutes walking distance (6MWD), quality of life (asassessed by questionnaire), cardiopulmonary exercise testing and/or peakVO2.

Comparison of results of different drug therapies (in combination withdenervation) is optionally performed to determine a particularlyeffective drug or drug combination, in combination with denervation.

Example 2 Effect of Denervation of Sympathetic Nerves in Combinationwith Drug Therapy on Pulmonary Arterial Hypertension in Randomized Study

The clinical effectiveness of denervation of sympathetic nervessurrounding the pulmonary vasculature in the treatment of PAH isevaluated using a randomized, single blind study. Denervation iseffected using ultrasonic energy, optionally using a TherapeuticIntra-Vascular Ultra-Sound (TIVUS™) system, with some of the patients(e.g., about half) undergoing a sham treatment with the ultrasonicsystem, as a control group.

Adult patients (e.g., about 120 patients) with idiopathic PAH, PAHassociated with connective tissue disease, anorexigen-induced PAH and/orheritable PAH, are selected according to the criteria describedhereinabove, on a stable drug regimen (as defined hereinabove) of atleast two PAH-specific medications. Variables which are determined inthe course of the study (in comparison with baseline values) include:

a) Cardiac MRI parameters relating to right ventricular (RV) function(e.g., at 6 and/or 12 months);

b) Peak VO₂ as evaluated by CPET (cardiopulmonary exercise testing)(e.g., at 6 and/or 12 months);

c) NT-pro BNP (N-terminal prohormone of brain natriuretic peptide) serumlevels (e.g., at 6 and/or 12 months);

d) Activity monitored using an actigraphy device (e.g., at 6 and/or 12months);

e) Quality of life, as determined by emPHasis questionnaire (e.g., at 6and/or 12 months); and/or

f) Long-term surveillance (e.g., at 2 and/or 3 years) for determiningsurvival (or cause of mortality), hospitalization due to PAH,interventional or surgical procedures such as atrial septostomy or lungtransplantation, worsening of WHO functional class, and/or escalation ofdrug therapy.

Safety is optionally evaluated as described hereinabove (e.g., at up to12 months post-procedure).

Effectiveness of treatment is determined by evaluating change in rightventricular (RV) function as assessed by MRI (e.g., RV ejectionfraction, RV end diastolic and systolic volume, wall thickness, aorticflow, PA flow, and/or main, left and right PA diameter), change in peakVO₂, activity measured (e.g., by actigraphy) as steps per awake hours,change in quality of life, and/or NT-pro BNP serum levels.

Effectiveness of denervation in combination with any given drug therapy(e.g., combination of drugs) is optionally observed as improved patientcondition in denervation-treated group relative to sham treatment.

Improvement of patient condition is optionally evidenced as a reductionone or more of: right atrial pressure (RAP), right ventricle pressures(RVP), systolic pulmonary artery pressure (sPAP), mean pulmonary arterypressures (mPAP), pulmonary vascular resistance (PVR), and/or NT-pro-BNPlevels and/or

as an increase in one or more of: cardiac output (CO), cardiac index(CI), ejection fraction (EF), pulmonary distensability, exercisetolerance—6 minutes walking distance (6MWD), quality of life (asassessed by questionnaire), cardiopulmonary exercise testing and/or peakVO2.

Comparison of results of different drug therapies (in combination withdenervation) is optionally performed to determine a particularlyeffective drug or drug combination, in combination with denervation.

Example 3 Safety and Effect of Denervation of Sympathetic Nerves inCombination with Drug Therapy on Pulmonary Arterial Hypertension

The safety, performance and initial effectiveness of denervation ofsympathetic nerves surrounding the pulmonary vasculature for treatingPAH was evaluated according to procedures similar to those described inExample 1. Elements of a study are presented in FIG. 3. A flow chart fora study is presented in FIG. 4.

Denervation was effected using ultrasonic energy, using a TherapeuticIntra-Vascular Ultra-Sound (TIVUS™) system.

14 adult patients with PAH in WHO functional class II-III were tested,with stable PAH on a stable drug regimen (i.e., with no changes of doseor medication for a minimum of 3 months prior to enrollment) of twoPAH-specific medications other than parenteral prostanoids.

The denervation procedure lasted 20-30 minutes on average, usabilityfeedback from the operators was excellent, and no severe adverse eventswere recorded at 1, 4, 8 and 12 month follow-up; indicating thatdenervation using a TIVUS™ system is an easy to perform,straightforward, predictable and safe procedure. The number ofdenervation sites for each patient ranged from 6 to 16, according topatient anatomy.

11 of the patients continued their drug regimens for at least 4 monthsafter treatment, at which time the following were determined:

Hemodynamic changes from baseline, for mPAP, PVR, right atrial pressureand cardiac index;

6-minute walking distance (6MWD);

Activity monitored using an actigraphy device; and

Quality of life, as determined by emPHasis-10 questionnaire (2 patientswho did not complete 4 months of drug regimen were also included inquality of life analysis).

As shown in FIGS. 5A-5D, hemodynamic parameters were consistentlyimproved 4 months after denervation treatment in subjects undergoingdrug therapy for PAH, with mean pulmonary arterial pressure (mPAP) beingreduced by an average of about 14% (FIG. 5A), cardiac index values beingincreased by an average of about 2% (FIG. 5B), pulmonary vascularresistance (PVR) values being reduced by an average of about 15% (FIG.5C), and right atrial pressure being reduced by an average of about 20%(FIG. 5D), relative to baseline.

In addition, as shown in FIG. 6, 6-minute walking distance (6MWD)increased by an average of about 21% relative to baseline, 4 monthsafter denervation treatment in subjects undergoing drug therapy for PAH.

As shown in FIG. 7, subject activity (as determined by actigraphy)increased by an average of about 12% relative to baseline, 4 monthsafter denervation treatment in subjects undergoing drug therapy for PAH.

As shown in FIG. 8, subject emPHasis-10 questionnaire scores decreasedby an average of about 21% relative to baseline, indicating an increaseof quality of life.

The above results, showing improvement in subjects on a stable drugtherapy, indicate that denervation complements drug therapy of PAH,suggesting that denervation exhibit beneficial effects via a differentmechanism than do therapeutically active agents for PAH.

As shown in FIG. 9, pulmonary vascular resistance (PVR) were reduced 4months after denervation in subjects treated by an anticoagulant(warfarin, rivaroxaban, dabigatran, apixaban, edoxaban, enoxaparinand/or fondaparinux), but not in subjects not treated regularly by ananticoagulant.

This result indicates that denervation is particularly suitable for usein treating PAH in combination with anticoagulants, for example, in asubpopulation of subjects who are treated by anticoagulants.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

1. A method of treating pulmonary arterial hypertension in a subject inneed thereof, the method comprising: a) determining a responsiveness ofthe subject to at least one therapeutically active agent usable intreating pulmonary arterial hypertension; and b) effecting pulmonaryartery denervation in a subject responsive to said at least onetherapeutically active agent, thereby treating the pulmonary arterialhypertension.
 2. The method of claim 1, wherein said at least onetherapeutically active agent is selected from the group consisting of ananticoagulant, a prostacyclin receptor agonist, an endothelin inhibitor,and a guanylate cyclase activity enhancer.
 3. The method of claim 1,wherein said at least one therapeutically active agent comprises aprostacyclin receptor agonist.
 4. The method of claim 1, wherein said atleast one therapeutically active agent comprises an endothelininhibitor.
 5. The method of claim 1, wherein said at least onetherapeutically active agent comprises a guanylate cyclase activityenhancer.
 6. The method of claim 1, wherein said therapeutically activeagent comprises an anticoagulant.
 7. The method of claim 2, wherein saidanticoagulant is selected from the group consisting of warfarin,acenocoumarol, dicoumarol, ethylbiscoumacetate, phenprocoumon,tecarfarin, anisindione, fluindione, phenindione, atromentin, a heparin,fondaparinux, idraparinux, idrabiotaparinux, apixaban, betrixaban,darexaban, edoxaban, eribaxaban, letaxaban, otamixaban, rivaroxaban,hirudin, lepirudin, bivalirudin, desirudin, argatroban, inogatran,dabigatran, melagatran, ximelagatran, antithrombin, batroxobin,hementin, and vitamin E.
 8. The method of claim 2, wherein saidprostacyclin receptor agonist is selected from the group consisting ofprostacyclin (epoprostenol), iloprost, beraprost, treprostinil andselexipag.
 9. The method of claim 2, wherein said endothelin inhibitorcomprises a selective ET_(A) receptor antagonist.
 10. The method ofclaim 2, wherein said endothelin inhibitor comprises a dualET_(A)/ET_(B) receptor antagonist.
 11. The method of claim 2, whereinsaid guanylate cyclase activity enhancer is selected from the groupconsisting of sildenafil, tadalafil, vardenafil and riociguat.
 12. Themethod of claim 1, wherein effecting said pulmonary artery denervationcomprises thermally damaging nerve tissue associated with a mainpulmonary artery.
 13. The method according to claim 12, wherein saidthermally damaging nerve tissue comprises selectively damaging nervesthat are not coated by myelin, by emitting energy at a frequency,intensity and duration sufficient to damage only nerves that are notcoated by myelin, by producing a predetermined temperature profile inthe treated tissue, said temperature profile ranging between 47-57° C.14. The method according to claim 12, wherein said thermally damagingnerve tissue is effected by cryotherapy and/or by emitting energy fromat least one energy-emitting device introduced into the body.
 15. Themethod according to claim 14, wherein said energy is selected from thegroup consisting of ultrasound energy and monopolar or bipolarradiofrequency energy.
 16. The method according to claim 15, whereinsaid energy comprises unfocused ultrasound energy.
 17. The methodaccording to claim 14, wherein effecting said pulmonary arterydenervation comprises introducing a catheter device comprising said atleast one energy-emitting device into a main pulmonary artery lumen. 18.The method according to claim 14, wherein said energy-emitting device isa transceiver, and effecting said pulmonary artery denervation furthercomprises: receiving, using said at least one energy-emittingtransceiver, echo signals reflected from non-targeted tissue followingemission of energy by said at least one transceiver; analyzing saidreceived echo signals to identify at least one of a type and location ofsaid non-targeted tissue relative to said at least one transceiver; andemitting energy from said at least one transceiver in accordance withsaid analyzing, to modify nerve activity without substantially damagingsaid identified non-targeted tissue.
 19. The method according to claim14, wherein effecting said pulmonary artery denervation furthercomprises: positioning said at least one energy-emitting device withinthe left pulmonary artery, right pulmonary artery and/or pulmonaryartery trunk at a location which is in between the first bifurcation ofthe left pulmonary artery and the first bifurcation of the rightpulmonary artery, wherein said thermally damaging nerve tissue comprisesemitting energy having parameters selected to damage nerves only withina distance window of between 0.2 mm and 10 mm from the intimal aspect ofthe pulmonary artery wall when said at least one device is positioned atsaid location.
 20. A method of treating pulmonary arterial hypertensionin a subject in need thereof, the method comprising: a) effectingpulmonary artery denervation in the subject; and b) administering to thesubject at least one therapeutically active agent usable in treatingpulmonary arterial hypertension, wherein said administering is at asub-therapeutically effective amount, thereby treating the pulmonaryarterial hypertension.
 21. The method of claim 20, wherein saidadministering said sub-therapeutically effective amount comprisesadministering, subsequently to said denervation, a dosage of at leastone therapeutically active agent which is lower than a dosage of saidagent administered to the subject prior to said denervation.
 22. Themethod of claim 20, wherein said administering said sub-therapeuticallyeffective amount comprises administering, subsequently to saiddenervation, fewer therapeutically active agents than are administeredto the subject prior to said denervation, wherein at least twotherapeutically active agent usable in treating pulmonary arterialhypertension are administered to the subject prior to said denervation.23. The method of claim 20, wherein said at least one therapeuticallyactive agent is selected from the group consisting of an anticoagulant,a prostacyclin receptor agonist, an endothelin inhibitor, and aguanylate cyclase activity enhancer. 24-32. (canceled)
 33. The method ofclaim 20, wherein effecting said pulmonary artery denervation comprisesthermally damaging nerve tissue associated with a main pulmonary artery.34-40. (canceled)
 41. A method of treating pulmonary arterialhypertension in a subject in need thereof, the method comprisingeffecting pulmonary artery denervation in the subject, the method beingdevoid of administering to the subject a therapeutically active agentusable in the treatment of pulmonary arterial hypertension for a timeperiod of at least one month subsequent to said denervation, therebytreating the pulmonary arterial hypertension.
 42. The method of claim41, wherein the method is devoid of administering to the subject saidtherapeutically active agent usable in the treatment of pulmonaryarterial hypertension for a time period of at least one year subsequentto said denervation.
 43. The method of claim 41, wherein effecting saidpulmonary artery denervation comprises thermally damaging nerve tissueassociated with a main pulmonary artery. 44-50. (canceled)